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1
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Liang LF, Zhao JQ, Wu YF, Chen HJ, Huang T, Lu XH. SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1. World J Diabetes 2025; 16:101328. [PMID: 40093288 PMCID: PMC11885972 DOI: 10.4239/wjd.v16.i3.101328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/06/2024] [Accepted: 01/02/2025] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Diabetic macular edema (DME) is the most common cause of vision loss in people with diabetes. Tight junction disruption of the retinal pigment epithelium (RPE) cells has been reported to induce DME development. SMAD-specific E3 ubiquitin protein ligase (SMURF) 1 was associated with the tight junctions of cells. However, the mechanism of SMURF1 in the DME process remains unclear. AIM To investigate the role of SMURF1 in RPE cell tight junction during DME. METHODS ARPE-19 cells treated with high glucose (HG) and desferrioxamine mesylate (DFX) for establishment of the DME cell model. DME mice models were constructed by streptozotocin induction. The trans-epithelial electrical resistance and permeability of RPE cells were analyzed. The expressions of tight junction-related and autophagy-related proteins were determined. The interaction between insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and SMURF1 mRNA was verified by RNA immunoprecipitation (RIP). SMURF1 N6-methyladenosine (m6A) level was detected by methylated RIP. RESULTS SMURF1 and vascular endothelial growth factor (VEGF) were upregulated in DME. SMURF1 knockdown reduced HG/DFX-induced autophagy, which protected RPE cell tight junctions and ameliorated retinal damage in DME mice. SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor (WIF) 1 ubiquitination and degradation. IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner. CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation, which activated autophagy to inhibit RPE cell tight junctions, ultimately promoting DME progression.
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Affiliation(s)
- Li-Fang Liang
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Jia-Qi Zhao
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Yi-Fei Wu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Hui-Jie Chen
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Tian Huang
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Xiao-He Lu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
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2
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Wan JX, Wang YQ, Lan SN, Chen L, Feng MQ, Chen X. Research Progress in Function and Regulation of E3 Ubiquitin Ligase SMURF1. Curr Med Sci 2023; 43:855-868. [PMID: 37558865 DOI: 10.1007/s11596-023-2774-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 06/08/2023] [Indexed: 08/11/2023]
Abstract
Smad ubiquitylation regulatory factor 1 (Smurf1) is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase. Initially, Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein (BMP) pathway. After further research, several studies have confirmed that Smurf1 is widely involved in various biological processes, such as bone homeostasis regulation, cell migration, apoptosis, and planar cell polarity. At the same time, recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1's expression, activity, and substrate selectivity. In our review, a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.
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Affiliation(s)
- Ji-Xi Wan
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Yu-Qi Wang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Si-Na Lan
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Liu Chen
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Ming-Qian Feng
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
- College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xin Chen
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
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3
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Tian X, Chen Y, Peng Z, Lin Q, Sun A. NEDD4 E3 ubiquitin ligases: promising biomarkers and therapeutic targets for cancer. Biochem Pharmacol 2023:115641. [PMID: 37307883 DOI: 10.1016/j.bcp.2023.115641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/14/2023]
Abstract
Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy.
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Affiliation(s)
- Xianyan Tian
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Yifei Chen
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Ziluo Peng
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Qiong Lin
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Aiqin Sun
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China.
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4
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Souza-Costa LP, Andrade-Chaves JT, Andrade JM, Costa VV, Franco LH. Uncovering new insights into the role of the ubiquitin ligase Smurf1 on the regulation of innate immune signaling and resistance to infection. Front Immunol 2023; 14:1185741. [PMID: 37228615 PMCID: PMC10203584 DOI: 10.3389/fimmu.2023.1185741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 03/28/2023] [Indexed: 05/27/2023] Open
Abstract
Innate immunity is the body's first line of defense against infections. Innate immune cells express pattern recognition receptors in distinct cellular compartments that are responsible to detect either pathogens-associated molecules or cellular components derived from damaged cells, to trigger intracellular signaling pathways that lead to the activation of inflammatory responses. Inflammation is essential to coordinate immune cell recruitment, pathogen elimination and to keep normal tissue homeostasis. However, uncontrolled, misplaced or aberrant inflammatory responses could lead to tissue damage and drive chronic inflammatory diseases and autoimmunity. In this context, molecular mechanisms that tightly regulate the expression of molecules required for the signaling of innate immune receptors are crucial to prevent pathological immune responses. In this review, we discuss the ubiquitination process and its importance in the regulation of innate immune signaling and inflammation. Then, we summarize the roles of Smurf1, a protein that works on ubiquitination, on the regulation of innate immune signaling and antimicrobial mechanisms, emphasizing its substrates and highlighting its potential as a therapeutic target for infectious and inflammatory conditions.
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Affiliation(s)
- Luiz Pedro Souza-Costa
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Josiane Teixeira Andrade-Chaves
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juvana Moreira Andrade
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vivian Vasconcelos Costa
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luis Henrique Franco
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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5
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Iyengar PV, Marvin DL, Lama D, Tan TZ, Suriyamurthy S, Xie F, van Dinther M, Mei H, Verma CS, Zhang L, Ritsma L, ten Dijke P. TRAF4 Inhibits Bladder Cancer Progression by Promoting BMP/SMAD Signaling. Mol Cancer Res 2022; 20:1516-1531. [PMID: 35731212 PMCID: PMC9530648 DOI: 10.1158/1541-7786.mcr-20-1029] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/24/2022] [Accepted: 06/17/2022] [Indexed: 01/07/2023]
Abstract
Patients with bladder cancer often have a poor prognosis due to the highly invasive and metastatic characteristics of bladder cancer cells. Epithelial-to-mesenchymal transition (EMT) has been causally linked to bladder cancer invasion. The E3 ubiquitin ligase, tumor necrosis factor receptor-associated factor 4 (TRAF4) has been implicated as a tumor promoter in a wide range of cancers. In contrast, here we show that low TRAF4 expression is associated with poor overall survival in patients with bladder cancer. We show that the TRAF4 gene is epigenetically silenced and that ERK mediates TRAF4 phosphorylation, resulting in lower TRAF4 protein levels in bladder cancer cells. In addition, we demonstrate that TRAF4 is inversely correlated with an EMT gene signature/protein marker expression. Functionally, by manipulating TRAF4 expression, we show that TRAF4 regulates EMT genes and epithelial and invasive properties in bladder cancer cells. Transcriptomic analysis of dysregulated TRAF4 expression in bladder cancer cell lines revealed that high TRAF4 expression enhances the bone morphogenetic protein (BMP)/SMAD and inhibits the NF-κB signaling pathway. Mechanistically, we show that TRAF4 targets the E3 ubiquitin ligase SMURF1, a negative regulator of BMP/SMAD signaling, for proteasomal degradation in bladder cancer cells. This was corroborated in patient samples where TRAF4 positively correlates with phospho-SMAD1/5, and negatively correlates with phospho-NFκb-p65. Lastly, we show that genetic and pharmacologic inhibition of SMURF1 inhibits the migration of aggressive mesenchymal bladder cancer cells. IMPLICATIONS Our findings identify E3 ubiquitin ligase TRAF4 as a potential therapeutic target or biomarker for bladder cancer progression.
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Affiliation(s)
- Prasanna Vasudevan Iyengar
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands.,Corresponding Authors: Prasanna Vasudevan Iyengar, Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, Leiden 2333ZC, the Netherlands. Phone: 715-269-271; Fax: 715-268-270; E-mail: ; and Peter ten Dijke,
| | - Dieuwke Louise Marvin
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Dilraj Lama
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Stockholm, Sweden.,Bioinformatics Institute (A*STAR), Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Sudha Suriyamurthy
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Feng Xie
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.,Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Maarten van Dinther
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Chandra Shekhar Verma
- Bioinformatics Institute (A*STAR), Singapore.,Department of Biological Sciences, National University of Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore
| | - Long Zhang
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Laila Ritsma
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands
| | - Peter ten Dijke
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.,Oncode Institute, Utrecht, the Netherlands.,Corresponding Authors: Prasanna Vasudevan Iyengar, Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, Leiden 2333ZC, the Netherlands. Phone: 715-269-271; Fax: 715-268-270; E-mail: ; and Peter ten Dijke,
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6
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Kholmanskikh S, Singh S, Ross ME. Activation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1. Sci Rep 2022; 12:16493. [PMID: 36192543 PMCID: PMC9529947 DOI: 10.1038/s41598-022-19740-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 09/02/2022] [Indexed: 11/09/2022] Open
Abstract
Regulation of Rho GTPases remains a topic of active investigation as they are essential participants in cell biology and the pathophysiology of many human diseases. Non-degrading ubiquitination (NDU) is a critical regulator of the Ras superfamily, but its relevance to Rho proteins remains unknown. We show that RhoC, but not RhoA, is a target of NDU by E3 ubiquitin ligase, LNX1. Furthermore, LNX1 ubiquitination of RhoC is negatively regulated by LIS1 (aka, PAFAH1B1). Despite multiple reports of functional interaction between LIS1 and activity of Rho proteins, a robust mechanism linking the two has been lacking. Here, LIS1 inhibition of LNX1 effects on RhoGDI-RhoC interaction provides a molecular mechanism underpinning the enhanced activity of Rho proteins observed upon reduction in LIS1 protein levels. Since LNX1 and RhoC are only found in vertebrates, the LIS1-LNX1-RhoC module represents an evolutionarily acquired function of the highly conserved LIS1. While these nearly identical proteins have several distinct RhoA and RhoC downstream effectors, our data provide a rare example of Rho-isoform specific, upstream regulation that opens new therapeutic opportunities.
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Affiliation(s)
- Stanislav Kholmanskikh
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th St, Box 240, New York, NY, 10021, USA.
| | - Shawn Singh
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th St, Box 240, New York, NY, 10021, USA
| | - M Elizabeth Ross
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 413 East 69th St, Box 240, New York, NY, 10021, USA.
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7
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Gu Y, Gao H, Zhang H, John A, Zhu X, Shivaram S, Yu J, Weinshilboum RM, Wang L. TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer. Oncogene 2022; 41:4119-4129. [PMID: 35864174 PMCID: PMC9417995 DOI: 10.1038/s41388-022-02415-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022]
Abstract
The HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.
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Affiliation(s)
- Yayun Gu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Huanyao Gao
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Huan Zhang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - August John
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Xiujuan Zhu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Suganti Shivaram
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Jia Yu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Richard M Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Liewei Wang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
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8
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Ruan X, Zhang R, Li R, Zhu H, Wang Z, Wang C, Cheng Z, Peng H. The Research Progress in Physiological and Pathological Functions of TRAF4. Front Oncol 2022; 12:842072. [PMID: 35242717 PMCID: PMC8885719 DOI: 10.3389/fonc.2022.842072] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/26/2022] [Indexed: 11/22/2022] Open
Abstract
Tumour necrosis factor receptor-associated factor 4 (TRAF4) is a member of the TRAF protein family, a cytoplasmic bridging molecule closely associated with various immune functions. The physiological processes of TRAF4 are mainly involved in embryonic development, cell polarity, cell proliferation, apoptosis, regulation of reactive oxygen species production. TRAF4 is overexpressed in a variety of tumors and regulates the formation and development of a variety of tumors. In this review, we summarize the physiological and pathological regulatory functions of TRAF4 and focus on understanding the biological processes involved in this gene, to provide a reference for further studies on the role of this gene in tumorigenesis and development.
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Affiliation(s)
- Xueqin Ruan
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Rong Zhang
- Division of Cancer Immunotherapy, National Cancer Center Exploratory Oncology Research & Clinical Trial Center, Chiba, Japan
| | - Ruijuan Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Hongkai Zhu
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Zhihua Wang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Canfei Wang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Zhao Cheng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Molecular Hematology, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
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9
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Roberts JZ, Crawford N, Longley DB. The role of Ubiquitination in Apoptosis and Necroptosis. Cell Death Differ 2021; 29:272-284. [PMID: 34912054 PMCID: PMC8817035 DOI: 10.1038/s41418-021-00922-9] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 12/29/2022] Open
Abstract
Cell death pathways have evolved to maintain tissue homoeostasis and eliminate potentially harmful cells from within an organism, such as cells with damaged DNA that could lead to cancer. Apoptosis, known to eliminate cells in a predominantly non-inflammatory manner, is controlled by two main branches, the intrinsic and extrinsic apoptotic pathways. While the intrinsic pathway is regulated by the Bcl-2 family members, the extrinsic pathway is controlled by the Death receptors, members of the tumour necrosis factor (TNF) receptor superfamily. Death receptors can also activate a pro-inflammatory type of cell death, necroptosis, when Caspase-8 is inhibited. Apoptotic pathways are known to be tightly regulated by post-translational modifications, especially by ubiquitination. This review discusses research on ubiquitination-mediated regulation of apoptotic signalling. Additionally, the emerging importance of ubiquitination in regulating necroptosis is discussed.
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Affiliation(s)
- Jamie Z Roberts
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
| | - Nyree Crawford
- Almac Discovery Laboratories, Health Sciences Building, Queen's University Belfast, Belfast, UK
| | - Daniel B Longley
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
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10
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Wang Y, Dai J, Zeng Y, Guo J, Lan J. E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications. Front Oncol 2021; 11:752604. [PMID: 34745984 PMCID: PMC8569917 DOI: 10.3389/fonc.2021.752604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023] Open
Abstract
Female breast cancer has become the most commonly occurring cancer worldwide. Although it has a good prognosis under early diagnosis and appropriate treatment, breast cancer metastasis drastically causes mortality. The process of metastasis, which includes cell epithelial–mesenchymal transition, invasion, migration, and colonization, is a multistep cascade of molecular events directed by gene mutations and altered protein expressions. Ubiquitin modification of proteins plays a common role in most of the biological processes. E3 ubiquitin ligase, the key regulator of protein ubiquitination, determines the fate of ubiquitinated proteins. E3 ubiquitin ligases target a broad spectrum of substrates. The aberrant functions of many E3 ubiquitin ligases can affect the biological behavior of cancer cells, including breast cancer metastasis. In this review, we provide an overview of these ligases, summarize the metastatic processes in which E3s are involved, and comprehensively describe the roles of E3 ubiquitin ligases. Furthermore, we classified E3 ubiquitin ligases based on their structure and analyzed them with the survival of breast cancer patients. Finally, we consider how our knowledge can be used for E3s’ potency in the therapeutic intervention or prognostic assessment of metastatic breast cancer.
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Affiliation(s)
- Yingshuang Wang
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawen Dai
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Youqin Zeng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinlin Guo
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Lan
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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11
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Cao Y, Yang Z, Chen Y, Jiang S, Wu Z, Ding B, Yang Y, Jin Z, Tang H. An Overview of the Posttranslational Modifications and Related Molecular Mechanisms in Diabetic Nephropathy. Front Cell Dev Biol 2021; 9:630401. [PMID: 34124032 PMCID: PMC8193943 DOI: 10.3389/fcell.2021.630401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/12/2021] [Indexed: 01/14/2023] Open
Abstract
Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by its complex pathogenesis, higher risk of mortality, and the lack of effective diagnosis and treatment methods. Many studies focus on the diagnosis and treatment of diabetes mellitus (DM) and have reported that the pathophysiology of DN is very complex, involving many molecules and abnormal cellular activities. Given the respective pivotal roles of NF-κB, Nrf2, and TGF-β in inflammation, oxidative stress, and fibrosis during DN, we first review the effect of posttranslational modifications on these vital molecules in DN. Then, we describe the relationship between these molecules and related abnormal cellular activities in DN. Finally, we discuss some potential directions for DN treatment and diagnosis. The information reviewed here may be significant in the design of further studies to identify valuable therapeutic targets for DN.
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Affiliation(s)
- Yu Cao
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
| | - Zhao Yang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhen Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Baoping Ding
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, China
| | - Haifeng Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
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12
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Hsu CH, Tomiyasu H, Liao CH, Lin CS. Genome-wide DNA methylation and RNA-seq analyses identify genes and pathways associated with doxorubicin resistance in a canine diffuse large B-cell lymphoma cell line. PLoS One 2021; 16:e0250013. [PMID: 33961622 PMCID: PMC8104391 DOI: 10.1371/journal.pone.0250013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 03/29/2021] [Indexed: 12/15/2022] Open
Abstract
Doxorubicin resistance is a major challenge in the successful treatment of canine diffuse large B-cell lymphoma (cDLBCL). In the present study, MethylCap-seq and RNA-seq were performed to characterize the genome-wide DNA methylation and differential gene expression patterns respectively in CLBL-1 8.0, a doxorubicin-resistant cDLBCL cell line, and in CLBL-1 as control, to investigate the underlying mechanisms of doxorubicin resistance in cDLBCL. A total of 20289 hypermethylated differentially methylated regions (DMRs) were detected. Among these, 1339 hypermethylated DMRs were in promoter regions, of which 24 genes showed an inverse correlation between methylation and gene expression. These 24 genes were involved in cell migration, according to gene ontology (GO) analysis. Also, 12855 hypermethylated DMRs were in gene-body regions. Among these, 353 genes showed a positive correlation between methylation and gene expression. Functional analysis of these 353 genes highlighted that TGF-β and lysosome-mediated signal pathways are significantly associated with the drug resistance of CLBL-1. The tumorigenic role of TGF-β signaling pathway in CLBL-1 8.0 was further validated by treating the cells with a TGF-β inhibitor(s) to show the increased chemo-sensitivity and intracellular doxorubicin accumulation, as well as decreased p-glycoprotein expression. In summary, the present study performed an integrative analysis of DNA methylation and gene expression in CLBL-1 8.0 and CLBL-1. The candidate genes and pathways identified in this study hold potential promise for overcoming doxorubicin resistance in cDLBCL.
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Affiliation(s)
- Chia-Hsin Hsu
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Hirotaka Tomiyasu
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Chi-Hsun Liao
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Chen-Si Lin
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
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13
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TRAF4/6 Is Needed for CD44 Cleavage and Migration via RAC1 Activation. Cancers (Basel) 2021; 13:cancers13051021. [PMID: 33804427 PMCID: PMC7957764 DOI: 10.3390/cancers13051021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 01/02/2023] Open
Abstract
The hyaluronan receptor CD44 can undergo proteolytic cleavage in two steps, leading to the release of its intracellular domain; this domain is translocated to the nucleus, where it affects the transcription of target genes. We report that CD44 cleavage in A549 lung cancer cells and other cells is promoted by transforming growth factor-beta (TGFβ) in a manner that is dependent on ubiquitin ligase tumor necrosis factor receptor-associated factor 4 or 6 (TRAF4 or TRAF6, respectively). Stem-like A549 cells grown in spheres displayed increased TRAF4-dependent expression of CD44 variant isoforms, CD44 cleavage, and hyaluronan synthesis. Mechanistically, TRAF4 activated the small GTPase RAC1. CD44-dependent migration of A549 cells was inhibited by siRNA-mediated knockdown of TRAF4, which was rescued by the transfection of a constitutively active RAC1 mutant. Our findings support the notion that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients.
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14
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Sinha A, Iyengar PV, ten Dijke P. E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression. Int J Mol Sci 2021; 22:E476. [PMID: 33418880 PMCID: PMC7825147 DOI: 10.3390/ijms22020476] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023] Open
Abstract
Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.
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Affiliation(s)
| | | | - Peter ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.S.); (P.V.I.)
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15
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Xia Q, Li Y, Han D, Dong L. SMURF1, a promoter of tumor cell progression? Cancer Gene Ther 2020; 28:551-565. [PMID: 33204002 DOI: 10.1038/s41417-020-00255-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 10/14/2020] [Accepted: 10/29/2020] [Indexed: 12/20/2022]
Abstract
Overexpression of HECT-type E3 ubiquitin ligase SMURF1 is correlated with poor prognosis in patients with various cancers, such as glioblastoma, colon cancer, and clear cell renal cell carcinoma. SMURF1 acts as a tumor promoter by ubiquitination modification and/or degradation of tumor-suppressing proteins. Combined treatment of Smurf1 knockdown with rapamycin showed collaborative antitumor effects in mice. This review described the role of HECT, WW, and C2 domains in regulating SMURF1 substrate selection. We summarized up to date SMURF1 substrates regulating different type cell signaling, thus, accelerating tumor progression, invasion, and metastasis. Furthermore, the downregulation of SMURF1 expression, inhibition of its E3 activity and regulation of its specificity to substrates prevent tumor progression. The potential application of SMURF1 regulators, specifically, wisely choose certain drugs by blocking SMURF1 selectivity in tumor suppressors, to develop novel anticancer treatments.
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Affiliation(s)
- Qin Xia
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yang Li
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Da Han
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Lei Dong
- School of Life Science, Beijing Institute of Technology, Beijing, China.
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16
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Sewduth RN, Baietti MF, Sablina AA. Cracking the Monoubiquitin Code of Genetic Diseases. Int J Mol Sci 2020; 21:ijms21093036. [PMID: 32344852 PMCID: PMC7246618 DOI: 10.3390/ijms21093036] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 12/26/2022] Open
Abstract
Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins. Understanding the function of monoubiquitination in normal physiology and pathology has important therapeutic implications, as alterations in the monoubiquitin pathway are found in a broad range of genetic diseases. This review highlights a link between monoubiquitin signaling and the pathogenesis of genetic disorders.
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Affiliation(s)
- Raj Nayan Sewduth
- VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; (R.N.S.); (M.F.B.)
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Maria Francesca Baietti
- VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; (R.N.S.); (M.F.B.)
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Anna A. Sablina
- VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium; (R.N.S.); (M.F.B.)
- Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
- Correspondence:
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17
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Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE. HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci 2020; 133:133/7/jcs228072. [PMID: 32265230 DOI: 10.1242/jcs.228072] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases play a critical role in various cellular pathways, including but not limited to protein trafficking, subcellular localization, innate immune response, viral infections, DNA damage responses and apoptosis. To date, 28 HECT E3 ubiquitin ligases have been identified in humans, and recent studies have begun to reveal how these enzymes control various cellular pathways by catalyzing the post-translational attachment of ubiquitin to their respective substrates. New studies have identified substrates and/or interactors with different members of the HECT E3 ubiquitin ligase family, particularly for E6AP and members of the neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) family. However, there still remains many unanswered questions about the specific roles that each of the HECT E3 ubiquitin ligases have in maintaining cellular homeostasis. The present Review discusses our current understanding on the biological roles of the HECT E3 ubiquitin ligases in the cell and how they contribute to disease development. Expanded investigations on the molecular basis for how and why the HECT E3 ubiquitin ligases recognize and regulate their intracellular substrates will help to clarify the biochemical mechanisms employed by these important enzymes in ubiquitin biology.
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Affiliation(s)
- Yaya Wang
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054.,Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Diana Argiles-Castillo
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Emma I Kane
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Anning Zhou
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054
| | - Donald E Spratt
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
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18
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Scott JL, Frick CT, Johnson KA, Liu H, Yong SS, Varney AG, Wiest O, Stahelin RV. Molecular Analysis of Membrane Targeting by the C2 Domain of the E3 Ubiquitin Ligase Smurf1. Biomolecules 2020; 10:biom10020229. [PMID: 32033048 PMCID: PMC7072158 DOI: 10.3390/biom10020229] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 12/18/2022] Open
Abstract
SMAD ubiquitination regulatory factor 1 (Smurf1) is a Nedd4 family E3 ubiquitin ligase that regulates cell motility, polarity and TGFβ signaling. Smurf1 contains an N-terminal protein kinase C conserved 2 (C2) domain that targets cell membranes and is required for interactions with membrane-localized substrates such as RhoA. Here, we investigated the lipid-binding mechanism of Smurf1 C2, revealing a general affinity for anionic membranes in addition to a selective affinity for phosphoinositides (PIPs). We found that Smurf1 C2 localizes not only to the plasma membrane but also to negatively charged intracellular sites, acting as an anionic charge sensor and selective PIP-binding domain. Site-directed mutagenesis combined with docking/molecular dynamics simulations revealed that the Smurf1 C2 domain loop region primarily interacts with PIPs and cell membranes, as opposed to the β-surface cationic patch employed by other C2 domains. By depleting PIPs from the inner leaflet of the plasma membrane, we found that PIP binding is necessary for plasma membrane localization. Finally, we used a Smurf1 cellular ubiquitination assay to show that the amount of ubiquitin at the plasma membrane interface depends on the lipid-binding properties of Smurf1. This study shows the mechanism by which Smurf1 C2 targets membrane-based substrates and reveals a novel interaction for non-calcium-dependent C2 domains and membrane lipids.
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Affiliation(s)
- Jordan L. Scott
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Cary T. Frick
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Kristen A. Johnson
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Haining Liu
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Sylvia S. Yong
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Allyson G. Varney
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Olaf Wiest
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (J.L.S.); (C.T.F.); (K.A.J.); (H.L.); (S.S.Y.); (A.G.V.); (O.W.)
| | - Robert V. Stahelin
- Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
- Correspondence: ; Tel.: +1-765-494-4152
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19
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Fu L, Cui CP, Zhang X, Zhang L. The functions and regulation of Smurfs in cancers. Semin Cancer Biol 2019; 67:102-116. [PMID: 31899247 DOI: 10.1016/j.semcancer.2019.12.023] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/10/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023]
Abstract
Smad ubiquitination regulatory factor 1 (Smurf1) and Smurf2 are HECT-type E3 ubiquitin ligases, and both Smurfs were initially identified to regulate Smad protein stability in the TGF-β/BMP signaling pathway. In recent years, Smurfs have exhibited E3 ligase-dependent and -independent activities in various kinds of cells. Smurfs act as either potent tumor promoters or tumor suppressors in different tumors by regulating biological processes, including metastasis, apoptosis, cell cycle, senescence and genomic stability. The regulation of Smurfs activity and expression has therefore emerged as a hot spot in tumor biology research. Further, the Smurf1- or Smurf2-deficient mice provide more in vivo clues for the functional study of Smurfs in tumorigenesis and development. In this review, we summarize these milestone findings and, in turn, reveal new avenues for the prevention and treatment of cancer by regulating Smurfs.
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Affiliation(s)
- Lin Fu
- Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China
| | - Chun-Ping Cui
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Xueli Zhang
- Department of General Surgery, Shanghai Fengxian Central Hospital Graduate Training Base, Fengxian Hospital, Southern Medical University, Shanghai, China.
| | - Lingqiang Zhang
- Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China; State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; Peixian People's Hospital, Jiangsu Province 221600, China.
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20
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Baloghova N, Lidak T, Cermak L. Ubiquitin Ligases Involved in the Regulation of Wnt, TGF-β, and Notch Signaling Pathways and Their Roles in Mouse Development and Homeostasis. Genes (Basel) 2019; 10:genes10100815. [PMID: 31623112 PMCID: PMC6826584 DOI: 10.3390/genes10100815] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/02/2019] [Accepted: 10/13/2019] [Indexed: 12/20/2022] Open
Abstract
The Wnt, TGF-β, and Notch signaling pathways are essential for the regulation of cellular polarity, differentiation, proliferation, and migration. Differential activation and mutual crosstalk of these pathways during animal development are crucial instructive forces in the initiation of the body axis and the development of organs and tissues. Due to the ability to initiate cell proliferation, these pathways are vulnerable to somatic mutations selectively producing cells, which ultimately slip through cellular and organismal checkpoints and develop into cancer. The architecture of the Wnt, TGF-β, and Notch signaling pathways is simple. The transmembrane receptor, activated by the extracellular stimulus, induces nuclear translocation of the transcription factor, which subsequently changes the expression of target genes. Nevertheless, these pathways are regulated by a myriad of factors involved in various feedback mechanisms or crosstalk. The most prominent group of regulators is the ubiquitin-proteasome system (UPS). To open the door to UPS-based therapeutic manipulations, a thorough understanding of these regulations at a molecular level and rigorous confirmation in vivo are required. In this quest, mouse models are exceptional and, thanks to the progress in genetic engineering, also an accessible tool. Here, we reviewed the current understanding of how the UPS regulates the Wnt, TGF-β, and Notch pathways and we summarized the knowledge gained from related mouse models.
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Affiliation(s)
- Nikol Baloghova
- Laboratory of Cancer Biology, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, 252 42 Vestec, Czech Republic.
| | - Tomas Lidak
- Laboratory of Cancer Biology, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, 252 42 Vestec, Czech Republic.
| | - Lukas Cermak
- Laboratory of Cancer Biology, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, 252 42 Vestec, Czech Republic.
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21
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Xie P, Wang X, Kong M, Bai X, Jiang T. TRAF4 promotes endometrial cancer cell growth and migration by activation of PI3K/AKT/Oct4 signaling. Exp Mol Pathol 2019; 108:9-16. [DOI: 10.1016/j.yexmp.2019.03.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 01/08/2019] [Accepted: 03/05/2019] [Indexed: 12/21/2022]
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22
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Zhu K, Tang Y, Xu X, Dang H, Tang LY, Wang X, Wang XW, Zhang YE. Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis. PLoS Biol 2018; 16:e3000091. [PMID: 30566427 PMCID: PMC6317813 DOI: 10.1371/journal.pbio.3000091] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 01/03/2019] [Accepted: 12/03/2018] [Indexed: 01/14/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of triglycerides (TG) in the liver and other metabolic syndrome symptoms, but its molecular genetic causes are not completely understood. Here, we show that mice deficient for ubiquitin ligase (E3) Smad ubiquitin regulatory factor 1 (Smurf1) spontaneously develop hepatic steatosis as they age and exhibit the exacerbated phenotype under a high-fat diet (HFD). Our data indicate that loss of Smurf1 up-regulates the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes involved in lipid synthesis and fatty acid uptake. We further show that PPARγ is a direct substrate of Smurf1-mediated non-proteolytic lysine 63 (K63)-linked ubiquitin modification that suppresses its transcriptional activity, and treatment of Smurf1-deficient mice with a PPARγ antagonist, GW9662, completely reversed the lipid accumulation in the liver. Finally, we demonstrate an inverse correlation of low SMURF1 expression to high body mass index (BMI) values in human patients, thus revealing a new role of SMURF1 in NAFLD pathogenesis.
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Affiliation(s)
- Kun Zhu
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Yi Tang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Xuan Xu
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Hien Dang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Liu-Ya Tang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Xiang Wang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ying E. Zhang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
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23
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Zhu S, Jin J, Gokhale S, Lu AM, Shan H, Feng J, Xie P. Genetic Alterations of TRAF Proteins in Human Cancers. Front Immunol 2018; 9:2111. [PMID: 30294322 PMCID: PMC6158389 DOI: 10.3389/fimmu.2018.02111] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 08/28/2018] [Indexed: 12/25/2022] Open
Abstract
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.
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Affiliation(s)
- Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Juan Jin
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Department of Pharmacology, Anhui Medical University, Hefei, China
| | - Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Angeli M. Lu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Haiyan Shan
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jianjun Feng
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education of the People's Republic of China, Fisheries College of Jimei University, Xiamen, China
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Member, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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Yu H, Li D, Zhou P, Li W. Smurf1-positive expression indicates favorable survival for resected non-small cell lung cancer patients. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:399-405. [PMID: 31938124 PMCID: PMC6957962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 10/28/2017] [Indexed: 06/10/2023]
Abstract
Recently studies have found that Smurf1 inhibits PIPKIγ-promoted lung cancer cell growth, tumorigenesis, and drug resistance through mediating the ubiquitination and degradation of PIPKIγi2. However, at present there is no study focused on the expression of Smurf1 protein as well as correlations among Smurf1 and lung cancer patients' survival. Therefore, we appraised Smurf1 expression by immmunohistochemistry and analyzed associations with prognosis in resected non-small cell lung cancer (NSCLC) patients. Overall, a number of 175 patients were enrolled in our study. We found that about 53 (30.2%) out of 175 NSCLC patients had Smurf1-pisitive expression. Smurf1-positive expression was significantly associated with lower lymph node metastasis (P=0.012). Smurf1-positive NSCLC patients had more favorable 5-year survival than patients with Smurf1-negative expression by univariate analysis (P=0.0002). Subgroup analysis found the same trend in lung adenocarcinoma (ADC, P=0.0006) other than lung squamous cell carcinoma (SCC, P=0.205). More interestingly, multivariate analysis also suggested that Smurf1-positive expression was significantly related to better overall survival (OS, P=0.003), independent of clinicopathological features and treatments of NSCLC patients. Unfortunately, we failed to observe statistically significant results when analyzed correlations among Smurf1 and NSCLC patients' progression-free survival (PFS, P=0.059). However, subgroup analysis revealed that Smurf1-positive patients had more favorable PFS for lung ADC patients (P=0.011) other than lung SCC (P=0.754). From the above, we guess that Smurf1 should be closely related to tumor metastasis and serve as an independent predictor of favorable prognosis in resected NSCLC patients.
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Affiliation(s)
- He Yu
- Department of Respiratory Medicine, Critical Care Medicine, West China Hospital, Sichuan University Chengdu 610041, Sichuan Province, P. R. China
| | - Dan Li
- Department of Respiratory Medicine, Critical Care Medicine, West China Hospital, Sichuan University Chengdu 610041, Sichuan Province, P. R. China
| | - Ping Zhou
- Department of Respiratory Medicine, Critical Care Medicine, West China Hospital, Sichuan University Chengdu 610041, Sichuan Province, P. R. China
| | - Weimin Li
- Department of Respiratory Medicine, Critical Care Medicine, West China Hospital, Sichuan University Chengdu 610041, Sichuan Province, P. R. China
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Zhu S, Jin J, Gokhale S, Lu AM, Shan H, Feng J, Xie P. Genetic Alterations of TRAF Proteins in Human Cancers. Front Immunol 2018. [PMID: 30294322 DOI: 10.3389/fimmu.2018.02111/bibtex] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023] Open
Abstract
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.
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Affiliation(s)
- Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Juan Jin
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Department of Pharmacology, Anhui Medical University, Hefei, China
| | - Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Angeli M Lu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Haiyan Shan
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jianjun Feng
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education of the People's Republic of China, Fisheries College of Jimei University, Xiamen, China
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
- Member, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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26
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Tao Y, Sun C, Zhang T, Song Y. SMURF1 promotes the proliferation, migration and invasion of gastric cancer cells. Oncol Rep 2017; 38:1806-1814. [PMID: 28731194 DOI: 10.3892/or.2017.5825] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 07/06/2017] [Indexed: 11/06/2022] Open
Abstract
Smad ubiquitin regulatory factor 1 (SMURF1), a well-known E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Accumulating studies have shown that SMURF1 acts as an oncogenic factor in human malignancies. However, the clinical significance of SMURF1 and its role in gastric cancer (GC) remain unclear. The expression of SMURF1 was detected in 68 cases of GC and corresponding tumor-adjacent specimens. Our results revealed that SMURF1 was prominently overexpressed in GC specimens compared to corresponding tumor-adjacent tissues. Furthermore, increased levels of SMURF1 mRNA were also observed in GC cell lines. Clinicopathological detection ascertained that SMURF1-positive expression was associated with large tumor size, more lymph nodes and distant metastasis as well as advanced tumor-node-metastasis (TNM) stage of GC. Notably, GC patients with SMURF1 positive‑expressing tumors exhibited a significant decreased survival. Further experiments illustrated that SMURF1 knockdown significantly inhibited proliferation, migration and invasion of MGC-803 cells, while SMURF1 overexpression prominently promoted these behaviors in SGC-7901 cells. In vivo studies revealed that SMURF1 knockdown markedly inhibited tumor growth and liver metastasis of GC. Mechanically, SMURF1 inversely regulated the expression of DOC-2/DAB2 interactive protein (DAB2IP) in GC tissues and cells. Furthermore, DAB2IP restoration revealed similar effects to SMURF1 knockdown on MGC-803 cells with decreased proliferation, migration and invasion. In addition, the PI3K/Akt pathway and its downstream targets including c-Myc and ZEB1 were potentially involved in the oncogenic role of the SMURF1/DABIP axis. Collectively, the present study revealed the first evidence that SMURF1 can be potentially used as a clinical biomarker and target for novel treatment of human GC.
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Affiliation(s)
- Youmao Tao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Caixia Sun
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Tao Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yan Song
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
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27
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Iyengar PV. Regulation of Ubiquitin Enzymes in the TGF-β Pathway. Int J Mol Sci 2017; 18:ijms18040877. [PMID: 28425962 PMCID: PMC5412458 DOI: 10.3390/ijms18040877] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 04/15/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023] Open
Abstract
The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to dysregulate the pathway causing diseases such as bone disorders, cancer and metastasis. These enzymes and their counterparts are increasingly being tested as druggable targets, and thus a deeper understanding of the enzymes is required. This review summarizes the roles of specific ubiquitin modifying enzymes in the TGF-β pathway and how they are regulated.
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28
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Ke M, Mo L, Li W, Zhang X, Li F, Yu H. Ubiquitin ligase SMURF1 functions as a prognostic marker and promotes growth and metastasis of clear cell renal cell carcinoma. FEBS Open Bio 2017; 7:577-586. [PMID: 28396841 PMCID: PMC5377408 DOI: 10.1002/2211-5463.12204] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/15/2017] [Accepted: 01/27/2017] [Indexed: 01/01/2023] Open
Abstract
Smad ubiquitin regulatory factor 1 (SMURF1), a recently identified E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Previous studies have reported that SMURF1 also functions as an oncogene in human cancers. However, the clinical value of SMURF1 and its role in clear cell renal cell carcinoma (ccRCC) are unknown. SMURF1 expression was analyzed in 100 cases of ccRCC and matched tumor‐adjacent specimens. SMURF1 was prominently overexpressed in ccRCC specimens compared with tumor‐adjacent specimens. Increased levels of SMURF1 were also observed in ccRCC cell lines. Clinicopathological detection verified that SMURF1 expression was associated with advanced tumor node metastasis stage, large tumor size and vascular invasion of ccRCC patients. Moreover, Kaplan–Meier analysis found that SMURF1 elevation led to adverse overall survival and disease‐free survival. Multivariate Cox regression analysis revealed that SMURF1 expression was an independent marker for prognosis prediction. Further experiments illustrated that SMURF1 knockdown significantly inhibited growth and metastasis of 769P cells, while SMURF1 overexpression promoted proliferation, migration and invasion in OSRC‐2 cells. Mechanistically, SMURF1 inversely regulated the expression of DAB2 interacting protein, which negatively mediated the activation of both the ERK/RSK1 and PI3K/AKT/mTOR pathways in ccRCC cells. Taken together, these results suggest that SMURF1 might be a promising biomarker and target for novel treatment of human ccRCC.
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Affiliation(s)
- Mang Ke
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
| | - Licai Mo
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
| | - Weilin Li
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
| | - Xianjun Zhang
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
| | - Feiping Li
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
| | - Hongyuan Yu
- Department of Urology Taizhou Hospital of Zhejiang Province Wenzhou Medical University Linhai Zhejiang Province China
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29
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Yao W, Wang X, Cai Q, Gao S, Wang J, Zhang P. TRAF4 enhances osteosarcoma cell proliferation and invasion by Akt signaling pathway. Oncol Res 2015; 22:21-28. [PMID: 25700355 PMCID: PMC7592778 DOI: 10.3727/096504014x14077751730351] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
TRAF4, or tumor necrosis factor receptor-associated factor 4, is overexpressed in several cancers, suggesting a specific role in cancer progression. However, its functions in osteosarcoma are unclear. This study aimed to explore the expression of TRAF4 in osteosarcoma tissues and cells, the correlation of TRAF4 to clinical pathology of osteosarcoma, as well as the role and mechanism of TRAF4 in osteosarcoma metastasis. The protein expression levels of TRAF4 in osteosarcoma tissues and three osteosarcoma cell lines, MG-63, HOS, and U2OS, were assessed. Constructed TRAF4 overexpression vectors and established TRAF4 overexpression of the U2OS cell line. Cell proliferation, cell invasion, protein levels, and TRAF4 phosphorylations were assessed following TRAF4 transfection, as well as the effects of TRAF4 siRNA on cell proliferation and invasion. The results show that TRAF4 protein levels in osteosarcoma tissues were significantly higher than that in normal bone tissues. Importantly, an obvious upregulation of TRAF4 was found in carcinoma tissues from patients with lung metastasis compared with patients without lung metastasis. Consistently, a similar increase in TRAF4 mRNA and protein was also demonstrated in the osteosarcoma cell lines MG-63, HOS, and U2OS compared to normal bone cells, hFOB1.19. When TRAF4 was overexpressed in U2OS cells, cell proliferation was significantly enhanced, accompanied by an increase in Ki67 expression and colony formation. Compared with the control and vector-treated groups, TRAF4 transfection increased the invasion potential of U2OS cells (p < 0.05). Interestingly, TRAF4 transfection significantly enhanced the phosphorylation of Akt. After blocking Akt with its specific siRNA, TRAF4-induced cell proliferation and invasion were dramatically attenuated. In summary, our findings demonstrated that TRAF4 enhances osteosarcoma cell proliferation and invasion partially by the Akt pathway. This work suggests that TRAF4 might be an important target in osteosarcoma.
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Affiliation(s)
- Weitao Yao
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
| | - Xin Wang
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
| | - Qiqing Cai
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
| | - Songtao Gao
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
| | - Jiaqiang Wang
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
| | - Peng Zhang
- Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina
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30
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Rousseau A, Tomasetto C, Alpy F. [TRAF4, a multifaceted protein involved in carcinoma progression]. Biol Aujourdhui 2015; 208:299-310. [PMID: 25840457 DOI: 10.1051/jbio/2014026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Indexed: 06/04/2023]
Abstract
Eukaryotic epithelial cells form a sheet of contiguous cells, called epithelium, by means of the establishment of well-developed junctional complexes. These junctional complexes ensure the cell cohesion in the tissue and separate the plasma membrane into an apical and a basolateral compartment. This apicobasal polarity, which is crucial for both the architecture and the function of epithelia, is mainly maintained by tight junctions (TJS). Indeed, TJS weakening or loss disrupts the integrity of the epithelium, a process participating to the formation and progression of carcinomas. It has recently been shown that TRAF4, a protein dynamically localized in TJS and commonly overexpressed in carcinomas, plays a variety of functions in tumor progression. Here, we review recent data implicating TRAF4 in carcinogenesis. First, the conserved TRAF proteins family will be presented, and then the molecular mechanism addressing TRAF4 to TJS which involves lipid binding by the TRAF domain will be described. The various roles of TRAF4 in carcinogenesis will be discussed. Finally, we will highlight the ability of all TRAF proteins to bind lipids and discuss its potential functional relevance.
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Affiliation(s)
- Adrien Rousseau
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
| | - Catherine Tomasetto
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
| | - Fabien Alpy
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
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31
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Zepp JA, Wu L, Qian W, Ouyang W, Aronica M, Erzurum S, Li X. TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation. THE JOURNAL OF IMMUNOLOGY 2015; 194:2826-37. [PMID: 25681341 DOI: 10.4049/jimmunol.1402647] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
IL-25 promotes type 2 immunity by inducing the expression of Th2-associated cytokines. Although it is known that the IL-25R (IL-17RB) recruits the adaptor protein ACT1, the IL-25R signaling mechanism remains poorly understood. While screening for IL-25R components, we found that IL-25 responses were impaired in Traf4 (-/-) cells. Administering IL-25 to Traf4 (-/-) mice resulted in blunted airway eosinophilia and Th2 cytokine production. Notably, IL-25R recruitment of TRAF4 was required for the ACT1/IL-25R interaction. Mechanistically, TRAF4 recruited the E3-ligase SMURF2, to degrade the IL-25R-inhibitory molecule DAZAP2. Silencing Dazap2 increased ACT1/IL-25R interaction and IL-25 responsiveness. Moreover, a tyrosine within the IL-25R elicited DAZAP2 interference. This study indicates that TRAF4-SMURF2-mediated DAZAP2 degradation is a crucial initiating event for the IL-25 response.
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Affiliation(s)
- Jarod A Zepp
- Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195
| | - Ling Wu
- Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106
| | - Wen Qian
- Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Wenjun Ouyang
- Department of Immunology, Genentech, South San Francisco, CA 94080; and
| | - Mark Aronica
- Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Serpil Erzurum
- Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Xiaoxia Li
- Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195;
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32
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Wang A, Wang J, Sun L, Jin J, Ren H, Yang F, Diao K, Wei M, Mi X. Expression of tumor necrosis factor receptor-assicated factor 4 correlates with expression of Girdin and promotes nuclear translocation of Girdin in breast cancer. Mol Med Rep 2015; 11:3635-41. [PMID: 25591657 DOI: 10.3892/mmr.2015.3211] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 08/01/2014] [Indexed: 11/06/2022] Open
Abstract
Overexpression of tumor necrosis factor receptor‑associated factor 4 (TRAF4) has been reported in several human malignancies; however its association with Girdin in breast cancer is unclear. The aim of the present study was to analyze the correlation, expression and nuclear and cytoplasmic localizations of TRAF4 and Girdin in breast cancer tissues. Tissue samples from 38 patients with breast cancer, the MCF‑10A normal mammary epithelial cell line, the MCF‑7 estrogen‑receptor (ER)‑positive and MDA‑MB‑231 ER‑negative breast cancer cell lines were used in the present study. The results demonstrated that cytoplasmic expression of TRAF4 was positively correlated with cytoplasmic expression of Girdin. Furthermore, coexpression of TRAF4 and Girdin was highest in tissue samples from patients with lymph node metastases. Girdin was observed to be predominantly expressed in the cytoplasm of breast cancer cells; however TRAF4 promoted its translocation to the nucleus. These findings suggest that cytoplasmic expression of TRAF4 may be a novel potential marker for cell migration in breast cancer.
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Affiliation(s)
- Ailian Wang
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Jian Wang
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lili Sun
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Juan Jin
- Department of Pathology, Shaanxi Baoji Centre Hospital, Baoji, Shaanxi 721008, P.R. China
| | - Huayan Ren
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Fan Yang
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Kexin Diao
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Minjie Wei
- Department of Pharmacology, Pharmaceutical College, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaoyi Mi
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China
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Wang M, Guo L, Wu Q, Zeng T, Lin Q, Qiao Y, Wang Q, Liu M, Zhang X, Ren L, Zhang S, Pei Y, Yin Z, Ding F, Wang HR. ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance. Nat Commun 2014; 5:4901. [PMID: 25249323 DOI: 10.1038/ncomms5901] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 08/02/2014] [Indexed: 11/09/2022] Open
Abstract
ATM- and RAD3-related (ATR)/Chk1 and ataxia-telangiectasia mutated (ATM)/Chk2 signalling pathways play critical roles in the DNA damage response. Here we report that the E3 ubiquitin ligase Smurf1 determines cell apoptosis rates downstream of DNA damage-induced ATR/Chk1 signalling by promoting degradation of RhoB, a small GTPase recognized as tumour suppressor by promoting death of transformed cells. We show that Smurf1 targets RhoB for degradation to control its abundance in the basal state. DNA damage caused by ultraviolet light or the alkylating agent methyl methanesulphonate strongly activates Chk1, leading to phosphorylation of Smurf1 that enhances its self-degradation, hence resulting in a RhoB accumulation to promote apoptosis. Suppressing RhoB levels by overexpressing Smurf1 or blocking Chk1-dependent Smurf1 self-degradation significantly inhibits apoptosis. Hence, our study unravels a novel ATR/Chk1/Smurf1/RhoB pathway that determines cell fate after DNA damage, and raises the possibility that aberrant upregulation of Smurf1 promotes tumorigenesis by excessively targeting RhoB for degradation.
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Affiliation(s)
- Meilin Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Lei Guo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Qingang Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Taoling Zeng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Qi Lin
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yikai Qiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Qun Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Mingdong Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Xin Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Lan Ren
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Sheng Zhang
- Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China
| | - Yihua Pei
- Central Laboratory, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China
| | - Zhenyu Yin
- Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China
| | - Feng Ding
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Hong-Rui Wang
- 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China [2] Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China
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Zhou F, Li F, Xie F, Zhang Z, Huang H, Zhang L. TRAF4 mediates activation of TGF-β signaling and is a biomarker for oncogenesis in breast cancer. SCIENCE CHINA-LIFE SCIENCES 2014; 57:1172-6. [DOI: 10.1007/s11427-014-4727-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 02/20/2014] [Indexed: 01/25/2023]
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35
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Rousseau A, Wilhelm LP, Tomasetto C, Alpy F. The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells. Tissue Barriers 2014; 2:e975597. [PMID: 25610759 PMCID: PMC4292048 DOI: 10.4161/21688370.2014.975597] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 10/07/2014] [Indexed: 11/19/2022] Open
Abstract
Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4), a protein localized in TJs in normal epithelial cells, is frequently overexpressed in carcinomas. We recently found that TRAF4 impedes TJ formation/stability and favors cell migration, 2 hallmarks of cancer progression. In addition TRAF4 contributes to the TGF-β-induced epithelial-mesenchymal transition (EMT), metastasis, and p53 destabilization. TRAF4 recruitment to TJs is a prerequisite for its biological function on TJ formation/stability and on cell migration. Interestingly, TRAF4 is targeted to TJs through lipid-binding. The trimeric TRAF domain of TRAF4 binds 3 phosphoinositide (PIP) molecules. These findings shed new light on the role of TRAF4 in cancer progression; they provide a novel link between lipid metabolism and cancer progression and support the notion that TRAF4 could be a relevant target for cancer therapies. TRAF4 belongs to a family of 7 human proteins involved in different biological processes, such as inflammation, immunity and embryonic development. While the lipid-binding ability of the TRAF domain is conserved among the whole TRAF protein family, its functional role remains to be established for the remaining TRAF proteins.
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Affiliation(s)
- Adrien Rousseau
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Functional Genomics and Cancer Department ; Illkirch, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Illkirch, France ; Centre National de la Recherche Scientifique (CNRS) ; Illkirch, France ; Université de Strasbourg ; Illkirch, France ; Present address: MRC Laboratory of Molecular Biology ; Cambridge, UK
| | - Léa P Wilhelm
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Functional Genomics and Cancer Department ; Illkirch, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Illkirch, France ; Centre National de la Recherche Scientifique (CNRS) ; Illkirch, France ; Université de Strasbourg ; Illkirch, France
| | - Catherine Tomasetto
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Functional Genomics and Cancer Department ; Illkirch, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Illkirch, France ; Centre National de la Recherche Scientifique (CNRS) ; Illkirch, France ; Université de Strasbourg ; Illkirch, France
| | - Fabien Alpy
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Functional Genomics and Cancer Department ; Illkirch, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Illkirch, France ; Centre National de la Recherche Scientifique (CNRS) ; Illkirch, France ; Université de Strasbourg ; Illkirch, France
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Zhang J, Li X, Yang W, Jiang X, Li N. TRAF4 promotes tumorigenesis of breast cancer through activation of Akt. Oncol Rep 2014; 32:1312-8. [PMID: 24993240 DOI: 10.3892/or.2014.3304] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 06/16/2014] [Indexed: 11/05/2022] Open
Abstract
Increasing evidence suggests that tumor necrosis factor receptor-associated factor 4 (TRAF4) is an oncogene which is frequently overexpressed in many human carcinomas. Although TRAF4 was originally identified in breast cancer, the underlying mechanism of TRAF4 in tumorigenesis remains largely unknown. In the present study, we found that TRAF4 was overexpressed in cancer cells, and RNA interference (RNAi)-mediated gene knockdown of TRAF4 decreased cell growth, cell migration and invasion. Next, we found that TRAF4 promoted cell survival kinase Akt membrane recruitment, which is essential for Akt activation. Furthermore, we demonstrated a direct interaction between Akt and TRAF4. Additionally, overexpression of constitutively activated Akt reversed cell growth arrest in TRAF4 gene-silenced cells. Taken together, our data indicate that TRAF4 plays an important role in tumorigenesis of breast cancer through direct interaction and activation of Akt, implying that TRAF4 may be a potential molecular target for breast cancer prevention and therapy.
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Affiliation(s)
- Jie Zhang
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Xiaorui Li
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University Xinxiang, Henan 453100, P.R. China
| | - Weilong Yang
- Department of Neurosurgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Xiaokui Jiang
- Department of General Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Na Li
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
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Wang A, Wang J, Ren H, Yang F, Sun L, Diao K, Zhao Z, Song M, Cui Z, Wang E, Wei M, Mi X. TRAF4 participates in Wnt/β-catenin signaling in breast cancer by upregulating β-catenin and mediating its translocation to the nucleus. Mol Cell Biochem 2014; 395:211-9. [DOI: 10.1007/s11010-014-2127-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 06/17/2014] [Indexed: 12/21/2022]
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Abstract
In this issue, Zhang et al. (2013) demonstrate that the ubiquitin ligase TRAF4 associates with the TGF-β receptors, rescuing them from degradation and ubiquitylating TAK1 to activate non-Smad signaling, which together promote metastasis of breast cancer cells.
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Affiliation(s)
- Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, 751 23 Uppsala, Sweden; Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden.
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TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. PLoS Biol 2013; 11:e1001726. [PMID: 24311986 PMCID: PMC3848981 DOI: 10.1371/journal.pbio.1001726] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 10/23/2013] [Indexed: 12/26/2022] Open
Abstract
The cancer-associated TRAF4 protein has a TRAF domain that is a bona fide phosphoinositide-binding domain and involved in the modulation of tight junctions and cell migration. Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is frequently overexpressed in carcinomas, suggesting a specific role in cancer. Although TRAF4 protein is predominantly found at tight junctions (TJs) in normal mammary epithelial cells (MECs), it accumulates in the cytoplasm of malignant MECs. How TRAF4 is recruited and functions at TJs is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to TJs. Of interest, this property is shared by the other members of the TRAF protein family. Indeed, the TRAF domain of all TRAF proteins (TRAF1 to TRAF6) is a bona fide PIP-binding domain. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer that binds up to three lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts as a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJs and favoring cell migration. Tumor necrosis factor (TNF) receptor-associated factor 4, also known as TRAF4, is an unusual member of the TRAF protein family. While TRAFs are primarily known as regulators of inflammation, antiviral responses, and apoptosis, research on TRAF4 has identified its involvement in development and cancer. Importantly TRAF4 overexpression has been associated with a poor prognosis in breast cancers. TRAF4 has multiple subcellular localizations: to the plasma membrane in tight junctions (TJs), cytoplasmic and nuclear. The recruitment mechanisms and the functional impact of these distinct localizations are not completely understood. Here we investigate how TRAF4 is recruited to TJs and its involvement in cell–cell contacts in mammary epithelial cells (MECs). We show that the TRAF domain of all TRAFs contains a lipid binding module, and that TRAF4 uses this domain to form a trimeric complex that associates with phosphoinositides at the plasma membrane. Moreover this interaction is necessary for its recruitment to TJs. Additionally, we show that through its interaction with lipids TRAF4 delays TJ assembly and increases cell migration. We propose that TRAF4 has an important function in cancer progression by destabilizing TJs and favoring cell migration.
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Deng S, Huang C. E3 ubiquitin ligases in regulating stress fiber, lamellipodium, and focal adhesion dynamics. Cell Adh Migr 2013; 8:49-54. [PMID: 24589622 DOI: 10.4161/cam.27480] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Recent discoveries have unveiled the roles of a complicated network of E3 ubiquitin ligases in regulating cell migration machineries. The E3 ubiquitin ligases Smurf1 and Cul/BACURD ubiquitinate RhoA to regulate stress fiber formation and cell polarity, and ASB2α ubiquitinates filamins to modulate cytoskeletal stiffness, thus regulating cell spreading and cell migration. HACE1, XIAP, and Skp1-Cul1-F-box bind to Rac1 and cause its ubiquitination and degradation, thus suppressing lamellipodium protrusions, while PIAS3, a SUMO ligase, activates Rac1 to promote lamellipodium dynamics. Smurf1 also enhances Rac1 activation but it does not ubiquitinate Rac1. Both Smurf1 and HECTD1 regulate focal adhesion (FA) assembly and (or) disassembly through ubiquitinating the talin head domain and phosphatidylinositol 4 phosphate 5-kinase type I γ (PIPKIγ90), respectively. Thus, E3 ubiquitin ligases regulate stress fiber formation, cell polarity, lamellipodium protrusions, and FA dynamics through ubiquitinating the key proteins that control these processes.
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Affiliation(s)
- Shishan Deng
- Markey Cancer Center and Department of Molecular & Biomedical Pharmacology; University of Kentucky; Lexington, KY USA
| | - Cai Huang
- Markey Cancer Center and Department of Molecular & Biomedical Pharmacology; University of Kentucky; Lexington, KY USA
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